Indiplon is the common chemical name of N-Methyl-N-[3-[3-[2-thienylcarbonyl]pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]acetamide, and its chemical structure is shown as follows:

Indiplon is a safe and effective drug for the treatment of insomnia or chronic insomnia, and it is a high-affinity allosteric potentiator of GABAA responses. U.S. Pat. No. 4,521,422 discloses the preparation of indiplon and its derivatives and their uses as anxiolytic, anticonvulsant, sedative-hypnotic and skeletal muscle relaxant agents. In U.S. Pat. No. 6,399,621, the use of indiplon for the prevention and treatment of insomnia, particularly for chronic insomnia is disclosed. Crystalline indiplon was obtained according to the procedures described in above references. Details for preparation of crystalline indiplon were described in Example 1 of U.S. Pat. No. 4,521,422 and examples of U.S. Pat. No. 6,399,621. Example 1 of U.S. Pat. No. 4,521,422 has a following statement: “a reaction mixture of 3-amino-1H-pyrazol-4-yl)phenyl-methanone and 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one in 25 mL of glacial acetic acid was refluxed for 6 hours and then the solvent was removed in vacuums giving a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried with anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization”. The obtained substance is subsequently confirmed as a mixture of crystalline Form-I and Form-II of indiplon, as described in Example 1 of U.S. Pat. No. 6,384,221.
U.S. Pat. Nos. 6,384,221 and 6,544,999 disclose two crystalline forms (designated as Form I and II) of indiplon. Publication US 2004/0116446 further discloses a third polymorphic form (designated as Form III) of indiplon.
All of references cited above completely failed to describe or disclose amorphous form of indiplon.
Recently, the difference in many aspects of solid-state properties such as solubility, dissolution and bioavailability of crystal (polymorphic) forms and amorphous forms of a given drug substance has been widely reported. Many drugs such as antibiotics, hypnotics, lipid and high blood pressure lowering agents display the ploymorphic forms, which include different physical state, crystalline state, liquid state and non-crystalline (amorphous) state.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem Pharm Bull, 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favored over another. An amorphous form of cefuroxime axietil is a good example for exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of amorphous form as the final drug substance for cefuroxime axietil pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability.
Indiplon is a substance that is practically insoluble in water, and the solubility of crystalline indiplon is only 20-30 μg/ml. Therefore, there is a need to search for a more soluble form of indiplon, and amorphous form of indiplon may be particularly desirable. As solubility of amorphous form of indiplon in water increases, its dissolution rate may be faster and bioavailability may be higher than crystalline indiplon. We have now surprisingly and unexpectedly discovered that a new form of indiplon, e.g., pure amorphous form of indiplon can be prepared by simple and reproducible processes.